Current Hematologic Malignancy Reports最新文献

Purpose of review: The therapeutic landscape for chronic lymphocytic leukemia (CLL) has undergone a complete makeover following the introduction of highly effective targeted therapies, beginning with ibrutinib which first attained regulatory approval for CLL in 2014.

Recent findings: In recent years, we have seen further refinement of therapeutic options with the development of newer-generation Bruton's tyrosine kinase inhibitors (BTKi) including acalabrutinib and zanubrutinib that improve upon the safety of ibrutinib. Additionally, venetoclax-based approaches, combined with anti-CD20 antibodies, have allowed for time-limited targeted therapeutic strategies which are particularly attractive for certain subsets of patients though have demonstrated efficacy across all subgroups. Lastly, there is an ongoing movement toward the development of time-limited strategies inclusive of both a BTKi and venetoclax that may further widen potential options. CLL patients requiring frontline therapy have a unique burden of choice between highly effective therapies that differ substantially with respect to side effect profiles and schedules. This review will focus on the frontline management of CLL in the setting of these rapidly changing options.

Purpose of review: This review presents recently published clinical trial data and ongoing investigations regarding the treatment of Richter's transformation (RT).

Recent findings: Recently, numerous approaches have been investigated for the treatment of RT including: traditional chemoimmunotherapy regimens combined with targeted agents such as BTKi and BCL2i; immunotherapy combined with targeted agents; non-covalent BTKis; bispecific T cell engagers; and CART therapy. In addition, various novel targeted agents are currently being studied for the treatment of RT in phase 1 and 2 clinical trials. Standard of care treatment with chemoimmunotherapy for RT has limited efficacy in achieving durable remissions. Here, we review recent data on the use of combination treatments and targeted agents in RT. Although some progress has been made in the investigation to optimize treatment of RT, further study is needed to evaluate long term outcomes of recently published trials and test efficacy of upcoming novel agents.

Purpose of review: Hematologic malignances more commonly affect older individuals and often present with advanced, higher risk disease than younger patients. Allogeneic and autologous hematopoietic cell transplantation is well-established treatment modalities with curative potential following either frontline treatments for these diseases or salvage therapy in the relapsed or refractory setting. More recently, novel cellular immunotherapy such as chimeric antigen receptor T-cell therapy has been shown to lead to high response rate and durable remission in many patients with advanced blood cancers.

Recent findings: Given unique characteristics of older patients, how best to deliver these higher-intensity and time sensitive treatment modalities for them remains challenging. Moreover, their short-term and potential long-term impact on their functional status, cognitive status, and quality of life may be significant considerations for many older patients. All these issues contributed to the lack of access and significant underutilization of these potential curative treatment strategies. In this review, we present up to date evidence to support potential benefits of transplantation and cellular therapy for older adults, their steady improving outcomes, and most importantly, highlight the use of geriatric assessment to help select appropriate older patients and optimize them prior to and following transplantation and cellular therapy. We specifically describe our approach at Memorial Sloan Kettering Cancer Center and encouraging early results from its implementation.

Purpose of review: Acute lymphoblastic leukemia (ALL) is a rare hematologic neoplasm in adults, with most cases defined by pathology related to abnormal B cell proliferation known as B-cell ALL. The course is challenging, with less-than-optimal survival outcomes, even with aggressive multiagent chemotherapy and consideration for stem cell transplantation. Novel therapies focused on targetable pathways are being investigated to improve outcomes while simultaneously decreasing toxicity. In our review, we aim to evaluate the utilization of blinatumomab in B-cell ALL and provide insight on how this guides our management.

Recent findings: Blinatumomab is a bispecific T-cell engager (BiTE) immunotherapy that neutralizes malignant cells by instigating CD3-positive T cells to target CD19-positive B cells. However, this therapy targets both malignant and non-malignant lymphocytes with potentially severe side effects such as cytokine release syndrome or neurotoxicity. Evidence evaluating utilization in the relapsed or refractory setting has been most supported; however, newer trials have also indicated improved survival in the frontline treatment of B-cell ALL. As this therapy is relatively new, the treatment team may include members who are less experienced with the typical treatment course and drug mechanics. This review synthesized available data investigating the effectiveness of blinatumomab effectiveness and its adverse events in addition to providing guidance on safe administration methods utilizing a multidisciplinary healthcare team. When care is coordinated in these settings, serious side effects can be recognized early, allowing for necessary intervention leading to improved quality of life and overall survival. Future research will continue to evaluate blinatumomab in different lines of therapy and expand its way into community settings.

Purpose of review: Acute lymphoblastic leukemia (ALL) is a widely heterogeneous disease in terms of genomic alterations, treatment options, and prognosis. While ALL is considered largely curable in children, adults tend to have higher risk disease subtypes and do not respond as favorably to conventional chemotherapy. Identifying genomic drivers of leukemogenesis and applying targeted therapies in an effort to improve disease outcomes is an exciting focus of current ALL research. Here, we review recent updates in ALL targeted therapy and present promising opportunities for future research.

Recent findings: With the utilization of next-generation sequencing techniques, the genomic landscape of ALL has greatly expanded to encompass novel subtypes characterized by recurrent chromosomal rearrangements, gene fusions, sequence mutations, and distinct gene expression profiles. The evolution of small molecule inhibitors and immunotherapies, and the exploration of unique therapy combinations are some examples of recent advancements in the field. Targeted therapies are becoming increasingly important in the treatment landscape of ALL to improve outcomes and minimize toxicity. Significant recent advancements have been made in the detection of susceptible genomic drivers and the use of novel therapies to target them.

Purpose of the review: This review aims to elucidate the transformative impact and potential of machine learning (ML) in the diagnosis, prognosis, and clinical management of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It further aims to bridge the gap between current advances of ML and their practical application in these diseases.

Recent findings: Recent advances in ML have revolutionized prognostication, diagnosis, and treatment of MDS and AML. ML algorithms have proven effective in predicting disease progression, optimizing treatment responses, and in the stratification of patient groups. Particularly, the use of ML in genomic and epigenomic data analysis has unveiled novel insights into the molecular heterogeneity of MDS and AML, leading to better-informed therapeutic strategies. Furthermore, deep learning techniques have shown promise in analyzing complex patterns in bone marrow biopsy images, providing a potential pathway towards early and accurate diagnosis. While still in the nascent stages, ML applications in MDS and AML signify a paradigm shift towards precision medicine. The integration of ML with traditional clinical practices could potentially enhance diagnostic accuracy, refine risk stratification, and improve therapeutic approaches. However, challenges related to data privacy, standardization, and algorithm interpretability must be addressed to realize the full potential of ML in this field. Future research should focus on the development of robust, transparent ML models and their ethical implementation in clinical settings.

Purpose of Review

Telomere biology disorders (TBD) are a group of genetic disorders characterized by premature shortening of telomeres, resulting in accelerated aging of somatic cells. This often leads to major multisystem organ dysfunction, and TBDs have become increasingly recognized as a significant contributor to numerous disease processes within the past 10–15 years. Both research and clinical practice in this field are rapidly evolving.

Recent Findings

A subset of patients with TBD suffers from interstitial lung disease, most commonly pulmonary fibrosis. Often, the clinical presentation is indistinguishable from other forms of lung fibrosis. There are no pathognomonic radiographic or histological features, and a high level of suspicion is therefore required. Telomere evaluation is thus crucial to establishing the diagnosis.

Summary

This review details the clinical presentation, objective evaluation, indicated genetic testing, and recommended management strategies for patients affected by interstitial lung disease associated with TBDs. Our goal is to empower pulmonologists and other healthcare professionals who care for these patients to provide appropriate and personalized care for this population.

Purpose of Review

Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive.

Recent Findings

Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis.

Summary

TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.

Purpose of review: The current review focuses on the preclinical development and clinical advances of natural killer (NK) cell therapeutics for hematologic malignancies and offers perspective on the unmet challenges that will direct future discovery in the field.

Recent findings: Approaches to improve or re-direct NK cell anti-tumor functions against hematologic malignancies have included transgenic expression of chimeric antigen receptors (CARs), administration of NK cell engagers including BiKEs and TriKEs that enhance antibody-dependent cellular cytotoxicity (ADCC) by co-engaging NK cell CD16 and antigens on tumors, incorporation of a non-cleavable CD16 that results in enhanced ADCC, use of induced memory-like NK cells alone or in combination with CARs, and blockade of NK immune checkpoints to enhance NK cytotoxicity. Recently reported and ongoing clinical trials support the feasibility and safety of these approaches. NK cell-based therapeutic strategies hold great promise as cost-effective, off-the-shelf cell therapies for patients with relapsed and refractory hematologic diseases.

Purpose of review: Mature T/NK-cell neoplasms comprise a heterogeneous group of diseases with diverse clinical, histopathologic, immunophenotypic, and molecular features. A clinically relevant, comprehensive, and reproducible classification system for T/NK-cell neoplasms is essential for optimal management, risk stratification, and advancing understanding of these diseases. Two classification systems for lymphoid neoplasms were recently introduced: the 5th edition of World Health Organization classification (WHO-HAEM5) and the 2022 International Consensus Classification (ICC). In this review, we summarize the basic framework and updates in the classification of mature T/NK-cell neoplasms.

Recent findings: WHO-HAEM5 and ICC share basic concepts in classification of T/NK-cell neoplasms, emphasizing integration of clinical presentation, pathology, immunophenotype, and genetics. Major updates in both classifications include unifying nodal T-follicular helper-cell lymphomas into a single entity and establishing EBV-positive nodal T/NK-cell lymphoma as a distinct entity. However, some differences exist in taxonomy, terminology, and disease definitions. The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features.